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Abstract

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to
induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine.
However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate
the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely
neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that
subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates
proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad
libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic
administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute
administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is
mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant
AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia
and weight gain, and provide the basis for alternative targets to control energy balance.